Neuroendocrine mechanisms leading to novel control techniques of reproduction in livestock: Regulation of the GnRH pulse generator activity.

Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is essential for normal reproductive function in mammals. GnRH pulses from the hypothalamus drive pulsatile gonadotropin release from the anterior pituitary, thereby regulating gonadal activity. Classic studies in rhesus monkeys have demonstrated that intermittent physiological GnRH administration maintains luteinizing hormone and follicle-stimulating hormone secretion, whereas continuous infusion suppresses pituitary responsiveness, establishing the necessity of pulsatile GnRH release. The neural mechanism governing this rhythmic secretion is termed the GnRH pulse generator, a master regulator of the hypothalamus-pituitary-gonadal axis. The debate over its origin was resolved following the discovery of kisspeptin. Evidence from goats and genetically modified rodents indicates that kisspeptin neurons in the arcuate nucleus-termed KNDy neurons because they co-express kisspeptin, neurokinin B (NKB), and dynorphin A (Dyn)-constitute the GnRH pulse generator. NKB exerts stimulatory effects, whereas Dyn exerts inhibitory effects; their coordinated actions generate rhythmic GnRH release. GnRH pulse generator activity integrates diverse internal and external cues. Nutritional deficiency, inflammatory stress, and seasonal photoperiod suppress pulse frequency, whereas pheromonal stimuli, such as the male effect in ruminants, activate it. Central metabolic and neuroendocrine signals, including neuropeptide Y, cholecystokinin, melanocortin pathways, and serotonin, further modulate generator activity, linking energy balance and reproduction. Targeting these regulatory pathways offers promising strategies for artificial reproductive control in livestock and potentially wildlife, highlighting the GnRH pulse generator as a critical therapeutic and management target.